A Phase 1 study of the safety,tolerability,and pharmacokinetics of ALG-000184 (pevifoscorvir sodium),a novel Class E capsid assembly modulator,in healthy participants

Abstract

Background

Class E (empty) capsid assembly modulators (CAM-Es) inhibit HBV capsid assembly, pregenomic RNA encapsidation preventing formation the establishment of covalently closed circular HBV DNA (ccDNA). ALG-000184 (pevifoscorvir sodium), is a prodrug of the Class E CAM ALG-001075.

Methods

ALG-000184-201 was a Phase 1 randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability and pharmacokinetics of ALG-000184. Healthy participants (n = 8/cohort) received oral single-ascending doses (SAD) of ALG-000184 (40, 100, 250, and 500 mg) or placebo, and multiple-ascending daily doses (MAD) (150 mg and 250 mg) or placebo for 7 days.

Results

ALG-000184 was well tolerated by 48 participants who received single doses up to 500 mg and multiple daily doses up to 250 mg for 7 days. ALG-000184 was rapidly converted to the active moiety, ALG-001075. ALG-001075 had dose-proportional increase in plasma exposure, low-to-moderate variability (18%–34% CV for AUC_0-24), rapid absorption (median t_max 1–3.5 h), and biphasic distribution/elimination with terminal t½ 7–8 h and minimal accumulation (∼30%). A major oxidative metabolite, ALG-000302, was identified in plasma (∼17%–24% of ALG-001075). A high-fat/high-calorie meal did not significantly impact the plasma pharmacokinetics. No differences in pharmacokinetics between Asian and non-Asian participants were observed. A concentration QT analysis indicated no statistically significant change in ΔΔQTcF with plasma ALG-001075. Urinary excretion of ALG-001075 was low following single or multiple ALG-000184 doses.

Conclusions

ALG-000184 demonstrated good tolerability, safety and pharmacokinetic properties in healthy participants. The pharmacokinetic profile suggests that a daily dose of 100 mg or higher will provide efficacious exposures in patients with chronic HBV infection.

Clinical trial number

NCT04536337 (https://clinicaltrials.gov/study/NCT04536337).

Keywords

HBV CAM capsid assembly modulator chronic HBV infection single ascending multiple ascending healthy participants

Introduction

Chronic hepatitis B virus (HBV) infection remains a major public health threat, increasing the risk of progressive liver disease in the estimated 254 million affected individuals worldwide (2022).¹ Approved nucleos(t)ide analogue (NA) therapies suppress HBV DNA levels by inhibiting HBV DNA polymerase activity and have been shown to result in improvements to long-term clinical outcomes including the prevention of disease progression.^2–5 Sustained suppression of HBV DNA may halt or reverse liver inflammation and fibrosis, thereby preventing progression to cirrhosis and hepatocellular carcinoma.^6,7 However, most patients experience a rebound in HBV DNA after discontinuation of NA therapy, which can result in hepatitis flares and occasionally acute liver failure. Consequently, lifelong therapy is usually required to maintain clinical benefit. Although long-term NA therapy is generally well tolerated, viral suppression is incomplete and many patients with high baseline HBV DNA levels will still have detectable HBV DNA levels even after 8 years of therapy.⁸

There is a correlation between circulating HBV DNA levels and adverse clinical outcomes, in particularly the risk of developing hepatocellular carcinoma.⁹ Antivirals with alternative mechanisms of action are needed to completely suppress viral replication to achieve a sustained virologic response and functional cure.

Capsid assembly modulators (CAMs) are a widely studied class of small-molecule antiviral agents that inhibit capsid assembly and pregenomic RNA encapsidation. CAMs can be divided into two major classes: Class A, which causes aberrant core protein structures, and Class E which causes empty capsids with an otherwise normal morphology.^10–12 CAM-Es have dual mechanism of action (MOA): the primary MOA involves the acceleration of capsid assembly and inhibition of pregenomic RNA encapsidation, which leads to reductions in HBV DNA and HBV RNA. The secondary MOA involves the regulation of the formation of cccDNA in the nucleus.^10,13,14 This activity can be measured with surrogate markers such as reductions in HBeAg, HBcrAg, and HBsAg in serum.

Multiple CAMs have been evaluated in clinical trials and have demonstrated potent antiviral activity in terms of HBV DNA and HBV RNA suppression. In comparisons to NAs such as entecavir, they have demonstrated more rapid and deeper declines in HBV DNA and HBV RNA levels.^15,16 However, none have demonstrated significant reductions in HBsAg levels reflecting a lack of effectiveness in their ability to interfere with the formation and transcription of cccDNA. Consequently, in studies such as the phase 2 study of vebicorvir and entecavir where participants discontinued therapy after achieving HBV DNA and HBV RNA suppression, most experienced viral relapse and many also had transaminase flares.¹⁶

ALG-000184 (pevifoscorvir sodium) is a prodrug of a novel, potent Class E CAM, ALG-001075. In cell-based experiments, ALG-001075 has nanomolar, broad-spectrum antiviral activity of HBV isolates from genotypes A to J. In primary human hepatocytes, ALG-001075 demonstrated potent inhibition of viral replication as measured by decreases in HBV DNA, HBV RNA, HBsAg, and HBeAg indicating that ALG-001075 prevents viral replication by both pregenomic RNA encapsidation and, at higher concentrations, the establishment of cccDNA. Compared to single-digit nanomolar EC₅₀ values for HBV DNA suppression via inhibition of pregenomic RNA encapsidation (primary MOA), higher concentrations of ALG-001075 are required (EC₅₀ of 10.0–70.0 nM) to achieve inhibition of cccDNA formation (secondary MOA), as indicated by the inhibition of HBsAg, HBeAg, and intracellular HBV RNA when ALG-001075 was added with the inoculum. These results confirm the potent antiviral activity of ALG-001075 observed in cell culture and show potent activity via dual mechanisms of action.¹⁷

Based on the compelling results from these nonclinical studies, we designed the first-in-human, Phase 1 Study ALG-000184-201 to evaluate the safety, tolerability, and pharmacokinetics of the ALG-000184 in healthy participants. The findings from this trial served as a foundation for further clinical development of ALG-000184 in patients with chronic HBV infection.

Methods

Clinical study design

This Phase 1 study, ALG-000184-201, was a multi-part, double-blind, randomized, placebo-controlled, first-in-human, and first-in-patient trial to evaluate the safety, tolerability, pharmacokinetics and preliminary antiviral effect of orally administered ALG-000184 in single-ascending doses and multiple-ascending doses in healthy participants (Parts 1 and 2, respectively), and as multiple doses in participants with chronic HBV infection (Parts 3–5). Here, we report the results of Parts 1, and 2; Parts 3–5 will be reported separately. The study was conducted in compliance with Good Clinical Practices and the ethical guidelines of the 1975 Declaration of Helsinki.

After an approximately 6-week screening period (Day -42 to Day -2), the eligible participants were confined to the clinic site on Day -2 and discharged on Day 3. For Part 2, on Day 3, they were given a supply of the study drug for self-administration at home. Outpatient visits took place on Days 3–5, followed by confinement at the clinic site on Days 6 and 7, with discharge on Day 8. Participants were monitored for 1 week and 2 weeks after the last dose of ALG-000184 in Parts 1 and 2, respectively.

ALG-000184 administration

Part 1 consisted of 4 cohorts with eight participants per cohort who were randomized (3:1) to receive a single oral dose of 40, 100, 250, and 500 mg ALG-000184 or placebo. The starting dose of 40 mg was anticipated to achieve exposures of ALG-001075 that were within limits established in nonclinical toxicology studies and were projected to result in antiviral activity. In the 28-days repeat-dose studies in rat and dog, ALG-000184 was well tolerated. The no-observed-adverse-effect levels (NOAELs) from the repeat-dose toxicology studies were 50 mg/kg/day in rat and 25 mg/kg/day in dogs. The planned starting dose of 40 mg in Study ALG-000184-201 provided safety margins of ∼12- to 21-fold from the NOAELs. In addition, modelling and simulations were conducted to estimate human plasma exposures at the planned starting dose. Human pharmacokinetic (PK) parameters were estimated based on mouse, rat, monkey, and dog PK data. Briefly, a 2-compartment model best fit the available IV/PO plasma PK data from multiple species with allometric functions related to body weight, central, peripheral volume of distribution and clearance; no species effect on absorption rate or bioavailability was considered. At the starting dose of 40 mg, the projected human PK exposures were more than 118-fold lower than the NOAEL exposures observed in the 28-days rat and dog studies. Therefore, both human-equivalent dose and exposure-based calculations indicated sufficient margin of safety at the starting dose.

Participants in the 100 mg cohort were also administered a second single oral dose of ALG-000184 or placebo (per their original randomization assignment) in a fed state after a 7-day washout. Part 2 consisted of two cohorts where participants received multiple daily oral doses of 150 and 250 mg ALG-000184 or placebo for 7 days. Additionally, each cohort was required to enrol at least 3 Asian participants.

For each cohort in Part 1, two sentinel participants were randomized (1:1) and administered ALG-000184 or placebo to evaluate any potential acute dose-limiting adverse events (AEs). The Sponsor and Principal Investigator reviewed the safety data available for the 24 h post-dosing period to determine if it was safe to proceed with randomizing the remaining 6 participants.

Decisions regarding the doses to be assessed were made by the Study Review Committee, consisting of the Principal Investigator and sponsor representatives, after reviewing the pharmacokinetics and safety data from previous cohorts.

In Part 1, all doses were administered in fasting conditions. The effect of food on ALG-000184 pharmacokinetics was assessed in one cohort at the 100-mg dose where participants received a single dose of 100 mg in fasted state and after a washout of 7 days received 100 mg ALG-000184 in fed state. In Part 2, all doses were administrated in fed state.

In the fasting state, participants were required to take each dose of ALG-000184 or placebo with water after an overnight fast of at least 10 h. For the fed state, in the 100-mg cohort of Part 1, participants were instructed to eat a high-fat/high-calorie breakfast 30 min before the administration of ALG-000184 or placebo, and they were to finish the meal within 30 min.¹⁸ In both the fasted and fed states, participants were instructed to fast for at least 4 h after dosing.

Study population

Parts 1 and 2 enrolled males or women of non-childbearing potential, 18 to 55 years of age, with body mass index (BMI) from 18.0 to 32.0 kg/m², including extremes. Participants were required to have no clinically significant abnormalities on medical history, physical examination, medical history, 12-lead electrocardiogram (ECG) in triplicate, and laboratory tests. Key exclusion criteria included chronic infections of hepatitis viruses and HIV, any acute infection including SARS-CoV-2, and any other infection that may interfere with the study conduct or its interpretation. The complete inclusion and exclusion criteria can be found in the protocol (supplementary materials).

Pharmacokinetic assessments

The plasma and urinary concentration analysis of the prodrug ALG-000184, the parent compound of ALG-001075, and the major oxidative metabolite ALG-000302 were evaluated after ALG-000184 was administered orally. The concentrations of the analytes in plasma and urine were determined with a validated liquid chromatography–tandem mass spectrometry method.

Safety

Safety assessments, including physical examinations, vital signs, 12-lead ECGs, Holter monitoring, clinical laboratory measurements (serum chemistry, coagulation, haematology, and urinalysis), and pregnancy tests were performed at specified timepoints throughout the study.

All AEs were recorded from the time of consent through the final follow-up visit regardless of intensity (mild, moderate, or severe), seriousness, or relationship to ALG-000184. All AEs and serious adverse events (SAEs) were coded using the Medical Dictionary for Regulatory Activities (MedDRA), Version 23.0. All non-serious and serious AEs were followed until the event resolved or stabilized and was not expected to further resolve, or an alternative therapy was established. Changes in objective findings such as laboratory test results, physical examinations, or 12-lead ECGs were considered AEs only if they were associated with accompanying symptoms, required medical or surgical intervention, led to discontinuation from the study, required significant additional concomitant drug treatment or other therapy, or were considered clinically significant by the Investigator. AEs were evaluated and documented using the grading scales contained in the Division of AIDS Version 2.1 July 2017.

Safety oversight

The Study Review Committee provided safety oversight at regular and ad hoc Data Review Meetings, where they provided guidance on ongoing study management by reviewing emerging data and recommending actions deemed necessary for the continued protection of study participants.

Data analysis

No formal sample size was calculated in this first-in-human Phase 1 study because there was no statistical hypothesis testing. The proposed sample sizes for each study part were typical for studies at this phase of development and were deemed sufficient to evaluate the study objectives.

The plasma PK parameters for ALG-000184, ALG-001075, and the metabolite ALG-000302 were determined by standard non-compartmental methods in WinNonlin^®, V8.4.0 (Certara USA, Inc; Princeton, NJ, USA). The pharmacokinetic set consisted of all participants who received any amount of ALG-000184 and had quantifiable plasma PK concentration data of ALG-001075 (and other metabolites if applicable) that allowed for the characterization of a PK profile. To estimate the first-order terminal elimination rate constant (λ_z) linear regression of concentration in natural logarithmic scale versus time was performed using at least three data points. The linear up log down trapezoidal method was used in the computation of all AUC values. Participants with AUC% extrapolation >20% were excluded from the calculation of all elimination-related parameters (λ_z, AUC_0-inf, t_½, CL/F, and Vz/F) from the summary statistics. Analysis of dose proportionality of ALG-001075 exposures was conducted for maximum plasma concentrations (C_max) and area under the concentration versus time curves (AUC) using a power model. The power model is described as log(y) = log (β0) + β1 × log (dose), where y, β0, and β1 correspond to the pharmacokinetic parameters, proportionality constant, and exponent, respectively. Dose proportionality is implied if the 90% confidence interval (CI) for β1 falls between 0.7 and 1.43. Analysis of food effect and ethnic sensitivity (Asian vs non-Asian healthy participants) on PK parameters (C_max and AUC) were performed using standard bioequivalence criteria at the same dose levels. For urine pharmacokinetics, the cumulative amount of drug excreted in urine (Ae), the fraction eliminated calculated as Ae/dose, and renal clearance, determined by the ratio of Ae/(plasma AUC_0-24), were reported.

Analyses were based on the intention-to-treat population in each cohort, which included all randomized participants. The safety set consisted of all randomized participants who received at least 1 dose of ALG-000184, and the data were analysed using SAS software version 9.2. A linear mixed effect model was used to explore the relationship between change from baseline in QTcF and time-matched plasma ALG-001075. The prediction of placebo-adjusted mean change from baseline in QTcF (ΔΔQTcF) and its corresponding two-sided 90% CI at each dose level was also provided.

Results

Disposition and demographics

Parts 1 and 2 of the study were conducted at a single clinical pharmacology unit (New Zealand Clinical Research, formerly Auckland Clinical Studies, New Zealand) between 20 October 2020 and 29 January 2021.

In Part 1 (SAD), 63 potential participants were consented and underwent screening against the eligibility criteria; 31 participants failed this process. The most common reasons included failure to provide informed consent (N = 17), renal dysfunction (N = 6), failure to meet ECG criterion (N = 3) and a history of drug misuse (N = 3) (Supplemental Figure 1). Thirty-two participants were enrolled and randomized (3:1 ratio) into 1 of 4 cohorts to receive a single dose of 40, 100, 250, or 500 mg of ALG-000184 (n = 24) or matching placebo (n = 8) in the fasted state. All 32 participants successfully completed the study per protocol and were included in the intent-to-treat and Safety Analysis Sets. Furthermore, all 24 participants who received ALG-000184 were included in the PK Analysis Set.

In Part 2 (MAD), 32 potential participants were consented and underwent screening against the eligibility criteria; 8 participants failed this process. The most common reasons included failure to provide informed consent (N = 2), and renal dysfunction (N = 2) (Supplemental Figure 1). Sixteen healthy volunteers were enrolled and randomized (3:1 ratio) into 1 of 2 cohorts to receive oral, once daily doses of 150 or 250 mg ALG-000184 (n = 12) or matching placebo (n = 4) for 7 days under fed conditions. Overall, 12 participants received ALG-000184 (6 participants/cohort) and 4 participants received placebo (2 participants/cohort). All 16 participants successfully completed the study per protocol and were included in the intent-to-treat and Safety Analysis Sets. All 12 participants administered ALG-000184 were included in the PK Analysis Set.

Overall, the baseline demographics of participants were comparable across dose levels in Part 1 and Part 2 (Table 1). Healthy volunteers in Part 1 had the median (min-max) age of 29.5 years (18–34), all were male, 50% were Asian, and the mean (SD) BMI was 22.94 kg/m² (2.96). In Part 2, the median age was 36.0 years (21–54), 83.3% of the participants were male, 50.0% were Asian, and the mean (SD) BMI was 24.83 kg/m² (2.44). Asian participants enrolled in the trial were of Chinese or Korean ethnicity.

Table 1.

Demographic characteristics of healthy participants enrolled in part 1 (SAD) and part 2 (MAD).

	Part 1 (SAD)					Part 2 (MAD)
	Cohort 1	Cohort 2	Cohort 3	Cohort 4	Pooled placebo	Cohort 1	Cohort 2	Pooled placebo
ALG-000184 dose	40	100	250	500	–	150	250	–
N	6	6	6	6	8	6	6	4
Age, years mean (SD)	27.5 (7.5)	30.3 (5.0)	27.8 (5.9)	32.5 (13.4)	28.0 (9.1)	35.2 (12.9)	36.5 (9.4)	25.5 (3.0)
Male, n (%)	6 (100)	6 (100)	6 (100)	6 (100)	8 (100)	5 (83)	5 (83)	4 (100)
Asian, n (%)	3 (50)	3 (50)	3 (50)	3 (50)	4 (50)	3 (50)	3 (50)	3 (75)
BMI, kg/m² (SD)	22.6 (3.9)	24.2 (2.9)	22.6 (2.7)	22.3 (2.7)	27.0 (2.8)	24.7 (1.7)	25.0 (3.2)	24.7 (1.9)

BMI = body mass index; MAD = multiple-ascending dose; SAD = single-ascending dose.

No protocol deviation led to the exclusion of participant data for analysis, and no protocol deviations related to COVID-19 occurred.

Safety

Of the 48 participants enrolled, 24 received a single dose of ALG-000184, 12 received multiple-ascending doses and 12 received placebo. No SAEs were reported, and no treatment-emergent adverse events (TEAEs) resulted in the premature discontinuation of study medication. No notable differences in TEAEs were observed between participants who were assigned to receive ALG-000184 or placebo. All TEAEs were mild in intensity regardless of treatment assignment or number of doses of ALG-000184 administered. The overall incidence of TEAEs was similar in participants who received single or multiple doses of ALG-000184 compared to placebo (Table 2). There was no evidence that the frequency or severity of TEAEs increased with increasing doses of ALG-000184. In most cases, TEAEs were only reported in one participant with the exception of 2 cases of nausea reported in the 250 mg ALG-000184 cohort. The TEAEs considered by the Investigator to be at least possibly related to ALG-000184 were headache (n = 1, 100 mg ALG-000184 cohort in Part 1), nausea and vomiting (n = 1, 250 mg ALG-000184 cohort in Part 2), and dry mouth (n = 1, 250 mg ALG-000184 cohort in Part 2).

Table 2.

Incidence of TEAEs in part 1 and part 2.

Part 1: Single-ascending dose	Cohort 1 40 mg, N = 6	Cohort 2100 mg, N = 6	Cohort 3250 mg, N = 6	Cohort 4500 mg, N = 6	Overall ALG-000184, N = 24	Overall placebo, N = 8
Participants with ≥1 TEAE, n (%) m	3 (50.0) 5	3 (50.0) 4	0	0	6 (25.0) 9	3 (37.5) 4
TEAEs in ≥1 participants, n (%) m
abdominal Discomfort	1 (16.7) 1	0	0	0	1 (4.2) 1	0
Fatigue	1 (16.7) 1	0	0	0	1 (4.2) 1	0
Contusion	0	1 (16.7) 1	0	0	1 (4.2) 1	2 (25.0) 2
Back pain	0	1 (16.7) 1	0	0	1 (4.2) 1	0
Joint noise	0	0	0	0	0	1 (12.5) 1
Myalgia	1 (16.7) 1	0	0	0	1 (4.2) 1	0
headache	0	1 (16.7) 1	0	0	1 (4.2) 1	0
Cough	1 (16.7)1	0	0	0	1 (4.2) 1	0
Oropharygeal pain	1 (16.7) 1	0	0	0	1 (4.2) 1	0
Papule	0	0	0	0	0	1 (12.5) 1
Rash	0	1 (16.7) 1	0	0	1 (4.2) 1	0

Part 2: Multiple-ascending doses	Cohort 1150 mg QD×7 days, N = 6	Cohort 2250 mg QD×7 days, N = 6	Overall ALG-000184, N = 12	Overall placebo, N = 4
Participants with ≥1 TEAE, n (%) m	2 (33.3) 3	3 (50.0) 7	5 (41.7) 10	3 (75.0) 4
TEAEs in ≥1 participants, n (%) m
Abdominal discomfort	0	0	0	1 (25.0) 1
Dry mouth	0	1 (16.7) 1	1 (8.3) 1	0
Nausea	0	2 (33.3) 2	2 (16.7) 2	0
Vomiting	0	1 (16.7) 1	1 (8.3) 1	0
Fatigue	0	0	0	1 (25.0) 1
Skin laceration	1 (16.7) 2	0	1 (8.3) 2	0
Sunburn	1 (16.7) 1	0	1 (8.3) 1	0
Back pain	0	0	0	1 (25.0) 1
Dizziness	0	1 (16.7) 2	1 (8.3) 2	0
Mood altered	0	1 (16.7) 1	1 (8.3) 1	0
Chromaturia	0	0	0	1 (25.0) 1

m = number of events, n = number of participants, N = total number of participants, QD = once daily, TEAE = treatment-emergent AE (AEs that occurred after the first dose of ALG-000184). If a participant had multiple occurrences of a TEAE, the participant was presented only once in the participants count (n) column for a given preferred term.

In Part 1, all treatment-emergent laboratory abnormalities were Grade 1 or Grade 2 except for 2 Grade 3 (severe) laboratory elevations experienced in 1 participant each: exercise-related creatine kinase elevation (n = 1 participant dosed with 40 mg ALG-000184) and LDL elevation (n = 1 participant dosed with placebo). In Part 2, all treatment-emergent laboratory abnormalities were Grade 1 or Grade 2, except for one Grade 3 triglycerides elevation observed in 1 participant dosed with 250 mg ALG-000184. No changes in serum creatinine levels or eGFR were observed.

There was no difference in safety between Asian and non-Asian participants (Supplemental Tables 1 and 2).

Plasma pharmacokinetics following single-ascending dose

Following oral administration of ALG-000184, ALG-001075, the active moiety, was the predominant analyte in systemic circulation. Plasma prodrug ALG-000184 concentrations were low (AUC molar ratio for ALG-000184/ALG-001075 = 0.12% at highest dose of 500 mg), indicating rapid and efficient conversion from ALG-000184 to ALG-001075. The mean plasma–time concentration plots for ALG-001075 following a single dose of 40–500 mg ALG-000184 oral administration in the fed/fasted state are shown in Figure 1 and the PK parameters are summarized in Table 3. The pharmacokinetics of ALG-001075 following ALG-000184 oral administration showed low variability between participants (18%–34% coefficient of variation for AUC_0-24). The plasma ALG-001075 concentration profiles indicate rapid absorption, with median time to reach maximum concentration (t_max) in plasma ranging from 1 to 3.5 h.

Figure 1.

Mean (+SD) Plasma Concentration-Time Profiles of ALG-001075 Following a Single Oral Dose of ALG-000184 (log-linear scale).

Table 3.

Geometric mean (%Geo CV) PK parameters of ALG-001075 after ALG-000184 single-ascending dose (Part 1) and multiple-ascending doses (Part 2).

ALG-000184 dose (mg)	Part 1: Single-ascending dose (N = 6/cohort)					Part 2: Multiple-ascending doses (N = 6/cohort)
	40	100		250	500	150		250
	Fasted	Fasted	Fed	Fasted	Fasted	1^st dose	7th dose	1st dose	7th dose
ALG-001075 PK parameters
C_max (ng/mL)	611 (20.6)	1377 (24.9)	1107 (24.6)	4150 (38.0)	5917 (23.5)	1736 (11.2)	1845 (21.5)	2840 (16.4)	3392 (34.5)
t_max (h)^a	1 (0.5, 3)	2 (0.5, 4)	3.5 (2, 6)	1 (0.5, 3)	2 (1, 4)	4 (2,4)	3 (2,4)	3 (2,4)	3 (2,4)
AUC_0-24 (ng∙h/mL)	4499 (18.0)	10665 (25.5)	10679 (28.1)	26378 (34.2)	47681 (28.8)	15,059 (21.2)	19,088 (31.5)	24,225 (27.5	31,075 (44.8)
C_24h (ng/mL)	42.0 (53.4)	116 (71.6)	141 (44.2)	251 (67.0)	400 (63.4)	204 (50.9)	297 (57.8)	247.2 (92.6)	387 (109.8)
AUC_0-inf (ng∙h/mL)	4986 (22.0)	12103 (30.1)	12425 (30.8)	29263 (36.1)	51774 (31.0)
CL_ss/F (L/h)	8.0 (22.0)	8.26 (30.1)	8.05 (30.8)	8.54 (36.1)	9.66 (31.0)
Vz/F (L)	84.8 (17.6)	90.2 (26.5)	92.7 (23.7)	88.7 (32.5)	94.3 (32.8)
t_1/2 (h)^b	7.41 (19.4)	7.69 (19.6)	8.09 (17.9)	7.30 (18.0)	6.79 (8.6)

^aMedian (minimum, maximum).

^bArithmetic Mean (%CV).

SD = standard deviation, T_max = time after dosing at which the maximum plasma concentration is reached, C_max = maximum plasma concentration after dosing, AUC_0-24 = Area under the drug concentration-time curve from time 0 (time of dosing) to 24h, AUC_0-inf = exposure (area under the curve) extrapolated from dosing to infinity, CL/F = apparent systemic clearance after oral dosing, Vz/F = apparent volume of distribution, t_1/2 = half-life, RAAUC = accumulation ratio based on AUC: RAAUC = D7/D1.

ALG-001075 had a biphasic distribution/elimination pattern, with median terminal t½ ranging from 7 to 8 h, supporting a once daily (QD) dosing regimen. The estimated proportionality coefficients were 0.94 (90% CI 0.83–1.06), 0.93 (90% CI 0.81–1.06), and 0.94 (90% CI 0.81–1.06) for AUC_0-24, AUC_0-inf, and C_max, respectively, indicating a dose-proportional increase in plasma ALG-001075 across the 40–500 mg dose range (Supplemental Figure 2). The PK profile of the metabolite, ALG-000302, was similar to that of ALG-001075, with plasma metabolite-to-parent ratio AUC_0-inf ≤24% in the evaluated ALG-000184 dose range of 40–500 mg (Supplemental Table 5).

A high-fat/high-calorie meal did not impact ALG-001075 plasma exposures. The geometric mean ratios (GMRs) (90% CI) of C_max, AUC_0-t and AUC_0-inf of ALG-001075 with fed versus fasted conditions were 0.8 (0.62–1.05), 1.03 (0.94–1.13) and 1.03 (0.93–1.13), respectively. The GMRs were close to 1 and the 90% CIs cover 1 for all PK parameters, indicating no statistically significant difference in plasma ALG-001075 between fed and fasted conditions.

Plasma pharmacokinetics following multiple-ascending doses

The mean plasma concentration-time plots for ALG-001075 following seven daily oral doses of 150 or 250 mg ALG-000184 in healthy volunteers (Part 2) are shown in Figure 2 and the PK parameters are summarized in Table 3. PK variability between participants was low to moderate (CV ∼ 21%–45%). Plasma ALG-001075 exposures increased dose proportionally and plasma accumulation was approximately 30% following 7 daily doses. The AUC molar ratio for ALG-000302/ALG-001075 was approximately 17% (Supplemental Table 3). Other minor oxidative metabolies, ALG-000300 and ALG-000306, were also quantified in human plasma. ALG-000300 was not detectable in plasma. ALG-000306 was quantitatively determined as a minor metabolite (<6% of ALG-001075) in plasma.

Figure 2.

Mean (+SD) plasma concentration-time profiles of ALG-001075 following multiple oral doses of ALG-000184 – part 2 (log-linear scale).

Ethnic sensitivity analysis: Pharmacokinetics

An analysis was conducted to compare the pharmacokinetics of Asian and non-Asian participants (Supplemental Table 2 and Supplemental Figure 3). Following daily multiple doses, PK variability between participants was low to moderate and comparable between single and multiple doses, with % CV for AUC_0-24 ranges 7%–49% for Asian and 4%–45% for non-Asian participants. Plasma accumulation in ALG-001075 following daily dosing of ALG-000184 was also similar between Asian and non-Asian participants. Minor differences in the pharmacokinetics of ALG-001075 and its metabolite, ALG-000302, were observed between Asians and non-Asian participants. However, after adjusting for body weight, there were no clinically meaningful ethnic differences in PK parameters between Asian and non-Asian participants.

Concentration-QTc analysis

No cardiac AEs were observed, and no TEAEs of prolonged QT interval were reported. A concentration-QTc analysis was conducted using ECG data collected in Parts 1 and 2. The parameter estimates from the linear mixed-effects model indicated the mean (90% CI) slope estimates of the relationship between placebo-corrected QTcF change from baseline versus plasma ALG-001075 concentrations was 0.00065 (−0.00008, 0.00138) ms/(ng/mL), indicating that QTcF increase was 0.65 ms for every 1000 ng/mL of ALG-001075. However, the slope was not statistically different from zero (p = .0786), suggesting the ΔΔQTcF did not vary with plasma ALG-001075 exposure. Based on the final concentration-QTc model, the upper bound of the two-sided 90% CI of the predicted placebo-corrected mean QTcF change from baseline (ΔΔQTcF) was <10 ms at the C_max at the projected therapeutic dose of 300 mg and a supratherapeutic dose of 500 mg, suggesting ALG-000184 does not have any clinically relevant effects on the QT interval (Supplemental Figure 4). Taken together, these results suggest that the risk of QTc prolongation with ALG-000184 is low and intensive ECG monitoring is not necessary for future studies.

Urinary excretion

Concentrations of ALG-001075 were detectable in urine through 96 h postdose and not detectable at 120 h in Part 1 and detectable through 24 h postdose in all participants in Part 2. The urine ALG-001075 pharmacokinetic parameters after single and multiple doses of ALG-000184 are shown in Supplemental Table 4. Overall, low fractions of ALG-001075 excreted in urine over 120 h postdose (≤8 %) for SAD cohorts and over 24 h postdose (≤9%) for MAD cohorts. The mean renal clearance of ALG-001075 ranged from 0.44 to 0.74 L/h across all cohorts, which suggests renal clearance is not a clinically relevant clearance mechanism of ALG-000184.

Discussion

This randomized, placebo-controlled first-in-human clinical study demonstrated that ALG-000184 has a good tolerability, safety, and PK profile in healthy participants who received a single dose up to 500 mg and multiple doses up to 250 mg for 7 days.

As chronic HBV infection is very prevalent in Asia-Pacific region, it was important to evaluate any potential impact of race on ALG-001075 pharmacokinetics. As no clinically relevant differences were observed in the PK profile of ALG-001075 between Asian and non-Asian participants the authors conclude that no dose adjustments will be necessary for these populations.

For other CAMs that were in clinical development, exposures at multiples above in vitro EC₉₀ have demonstrated significant decreases in HBV DNA in patients.^19–23 The target efficacious exposure for total plasma is generally based on the serum-shifted in vitro EC₉₀ for HBV DNA inhibition. The minimum human efficacious exposure was based on maintaining C_min in plasma concentration of ALG-001075 at least 3-fold above the antiviral in vitro EC₉₀, which maximizes the probability of viral suppression in all patients. Based on the above assumptions and utilizing the PK data from this study, the projected efficacious dose range that can maintain the plasma C_min above in vitro EC₉₀ for both primary and secondary mechanism is expected to be 100 mg to 300 mg QD orally. At the projected doses these plasma exposure ranges are predicted to provide total steady-state plasma C_min approximately 10 to 30-fold above the serum-shifted EC₉₀ ALG-001075 concentration, where the lower range is the minimum human efficacious exposure, and the higher range allows for exploration of optimal pharmacodynamic effects for patients.

If these exposures can be achieved in larger studies in participants with chronic HBV infection, then ALG-000184 has the potential to be utilized as a chronic suppressive therapy, with or without a NA, with the goal of achieving greater HBV DNA and RNA viral suppression, and/or as part of a finite curative treatment regimen where it could also help achieve HBsAg negativity.

Limitations of the study include that it was conducted in predominantly healthy male participants, and that the data were derived from a small sample size and short dosing period, which is typical of first-in-human-studies. This could limit the generalizability of these results to individuals with chronic HBV infection where long-term dose administration will be required. The pharmacokinetics of ALG-001075 may also be different in the disease state due to inflammatory changes in the liver. In addition, dosing for 7 days in a small cohort is not sufficient to identify less common adverse events which will require larger studies to evaluate. Finally, studies will be required in special populations, such as those with hepatic impairment, to determine if adjustments to the dosing regimen are necessary.

In conclusion, this first-in-human study demonstrated that ALG-000184 was well tolerated with a good safety and PK profile. The pharmacokinetics indicates a QD regimen that would not require dose adjustment with food or in Asian participants. The PK profile also identified an initial dose, 100 mg, that was subsequently used as the starting point for dose exploration in participants with chronic HBV infection.

Supplemental Material

Supplemental Material - A phase 1 study of the safety, tolerability, and pharmacokinetics of ALG-000184, a novel class E capsid assembly modulator, in healthy participants

Supplemental Material for A phase 1 study of the safety, tolerability, and pharmacokinetics of ALG-000184, a novel class E capsid assembly modulator, in healthy participants by Ed Gane, Christian Schwabe, Min Wu, Tse-I Lin, Lawrence Blatt, John Fry, Sushmita Chanda, and Kha Le in Antiviral Therapy.

Footnotes

Acknowledgements

The authors wish to acknowledge and thank Christopher Westland and the team at Novotech for their assistance in managing the logistics of the study, and Peggy Korn for her assistance in helping to manage draft the manuscript.

ORCID iDs

Ed Gane

Kha Le

Ethical considerations

The study reported here was conducted in compliance with Good Clinical Practices and the ethical guidelines of the 1975 Declaration of Helsinki. The protocol was approved by the Human Research Ethics Committee (HREC): Health and Disability Ethics Committee (HDEC), New Zealand.

Consent to participate

Each study participant provided written informed consent.

Author contributions

The authors contributed to the study design, collection and review of the data, writing, and review of the manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the sponsor, Aligos Therapeutics, Inc., South San Francisco, California, US.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors declared the following conflicts of interest with respect to the research, authorship, and/or publication of this article: • Min Wu, Kha Le, Tse-I Lin, Lawrence Blatt, Sushmita Chanda are the employees of Aligos and owned equity in the company. • John Fry was an employee of Aligos Therapeutics at the time of study conduct and owned equity in the company. • Ed Gane is a consultant for Aligos, Assembly, AusperBio, Gilead, GSK, Janssen, Roche, Surrozen, VIR, Virion, Precision Biosciences, Tune, and has given lectures sponsored AbbVie, Roche Diagnostics. In addition, grants are provided by AbbVie for community HepC Microelimination Programme.

Data Availability Statement

Aligos shares anonymized individual patient data upon request or as required by law or regulation with qualified external researchers based on submitted curriculum vitae and reflecting non-conflict of interest. The request proposal must also include a statistician. Approval of such requests is at the sponsor’s discretion and is dependent on the nature of the request, the merit of the research proposed, the availability of the data, and the intended use of the data. Data requests should be sent to kle@aligos.com.

Supplemental Material

Supplemental Material for this article is available online.

Appendix

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Supplementary Material

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